This study analyzed the factors causing and contributing to death in patients with the adult respiratory distress syndrome (ARDS). Two hundred seven patients were prospectively identified as being at risk for development of ARDS. Forty-seven patients developed ARDS, and the remaining 160 patients were used as a comparison control group. The severity of dysfunction in 8 organ systems and the presence of sepsis syndrome were determined by chart review after discharge or death. Sepsis syndrome was specifically defined by signs and laboratory tests reflecting infection or inflammation plus evidence of a deleterious systemic effect (hypotension, reduced systemic vascular resistance, or unexplained metabolic acidosis). Mortality was 68% in the ARDS group compared to 34% in the control group (p < 0.005). Only 16% (5 of 32) of deaths in the ARDS group were from irreversible respiratory failure. Most deaths in the first 3 days after entry into the study could be attributed to the underlying illness or injury. The majority of late deaths were related to sepsis syndrome. Of the 22 patients with ARDS who died after 3 days, 16 (73%) met our criteria for sepsis syndrome. There was a sixfold increase in sepsis syndrome after ARDS compared with that in the control group (p < 0.001). When sepsis syndrome preceded the ARDS, the abdomen was the predominant source, but when sepsis syndrome occurred after the onset of ARDS there was usually a pulmonary source. Our findings indicate that sepsis syndrome, rather than respiratory failure, is the leading cause of death in patients with ARDS.